Asymmetric Total Synthesis of the Rearranged Steroid Phomarol Enabled by a Biomimetic SN2' Cyclization.

Abstract

Phomarol is a structurally unusual 1(10 → 19)abeo-steroid with a pseudo-symmetrical cycloheptene-1,3-diol motif, an aromatic B ring, and a densely functionalized tetrahydropyran ring. Herein, we report a 13-step synthesis of this natural product from inexpensive sitolactone by means of a convergent fragment-coupling approach. Key transformations include a diastereoselective allylboration, a decarboxylative elimination, a Schönecker-Baran C-H hydroxylation, a biomimetic SN2' cyclization, and a late-stage 6π electrocyclization. Mechanistic studies indicate that the pivotal formation of the tetrahydropyran ring occurs via a silyl migration/intramolecular SN2' cyclization cascade rather than via an epoxide-opening process.